How Does a New Drug Get to Market?

The diagram below shows the major steps involved in developing a new drug and getting it to market.


 
These steps have not changed in any significant way since the process of commercial drug development began.  However, one of the trends to be aware of is the point where pharmaceutical companies and academia meet and collaborate.  Traditionally (up until the early 1990’s), that point was shortly after a ‘target’ was identified.  Researchers at academic institutions would approach (or be approached by) drug companies who would then begin the actual drug development process—primarily the ‘chemistry’ of developing a compound that would defeat or immobilize the target.
 
Today, pharmaceutical companies will typically not get involved until the pre-clinical work on a drug has been completed.  This leaves a huge gap for academia and the ‘not-for-profit’ healthcare sector to fill if new drugs to defeat cancer and other illnesses are to be developed.
 

Target Identification 

 

In the area of target identification, there are ‘established targets’—those targets that scientists have a good functional understanding of—and ‘new targets’—all other targets that are not considered established.  Typically new targets are newly-discovered proteins or proteins whose function has become clear as a result of basic scientific research. 

The majority of targets chosen today for drug discovery work are proteins.  Two classes predominate:  G-protein-coupled receptors (or GPCRs) and protein kinases. A kinase is an enzyme that changes a protein or molecule from an inactive form to an active form.

Screening and ‘Hit’ Discovery 


 
The term ‘drug discovery’ usually refers to the early stages of drug development after a target has been identified when hundreds, often thousands, of compounds are screened to see if they have any influence on the target.  High-throughput screening (HTS) is a process where large libraries of chemicals are tested to see if they have any effect on the target.  Those that do are called ‘hits’.
 
Another important part of HTS is referred to as cross-screening.  This is where the scientists determine how selective the chemical compounds are. The best compounds or best ‘hits’ are those that impact only the specified target and not related targets. Those that also impact related targets are more likely to have undesirable side effects.
 
What usually happens as a result of the HTS process is the identification of a group of compounds that have some degree of impact on the target.  Hopefully, they share some common chemical features which would allow medicinal chemists to improve on certain features and enhance the effectiveness of the compound on the target (and reduce any impact on other targets).
 
The favoured compounds would go forward to ‘in vitro’ testing (i.e., testing outside a living organism—usually a test tube) and then ‘in vivo’ testing (i.e., testing in a living organism—typically mice).  Emerging from this process is hopefully a ‘lead’ and a ‘backup’ compound, and they would be proposed for actual drug development.
 
HTS is not the only method of identifying ‘hits’, however.  Other approaches include:
 
  • Virtual high throughput screening, where screening is done using computer-generated models that attempt to match properties of known compounds with the target
  • Drug design, where the biological and physical properties of the target are studied, and a prediction is made of the sorts of chemical compounds that might ‘fit’ into an active site
  • The target identified will sometimes suggest use of a known compound or molecule that has certain desired properties.  Such a molecule might be something that could be extracted from a natural product, or even be a drug already on the market for treatment of a different or related disease.
  • Often what is needed as a drug remedy is a drug compound that will ‘adhere to’ the identified protein target.  So, the search for a compound becomes a search for a compound with a certain ‘shape’ that will fit or adhere to a target much like a baseball glove does to a baseball, or a key to a lock.

Lead Development 

Lead development is a ‘chemistry intensive’ stage of drug development where the lead compound(s) are refined and optimized. Medicinal chemists start synthesizing and testing related compounds using different methods.  Analogous compounds (derivatives of a parent compound that differ by only a single element) need to be examined and tested as they may have more potency or be more selective (i.e., have less impact on other targets).  They have to ensure that the compound they develop is going to be tolerable by humans. 

In preparation for the pre-clinical stage, the scientists will also turn their attention to the various ways that the drug could be administered (e.g., capsules, tablets, aerosol, intramuscular injectable, or intravenous) and effective and safe dosage levels.

Pre-Clinical 

 
The pre-clinical stage of new drug development includes a number of activities.  First, it is the stage of overall drug development that confirms the safety of the lead compound and identifies potential toxicities.
The requirements of various regulatory bodies must be adhered to, which usually includes a number of tests that determine the toxicity of a drug prior to human testing.  This includes tests that assess and measure the impact on major organs (heart, lungs, brain, kidney, liver and digestive system).
 
Some of these tests can be performed in vitro (test tube), but many will need to be performed on animals as the interplay of the drug with an ‘intact’ organism must be observed and measured in some way.
 
Pharmacokinetic issues (how a drug is absorbed by the body, distributed, metabolized, and eliminated) are studied in detail and tested thoroughly, and recommendations on the dose and schedule for use are made. 
 

Clinical Trials 

 
Clinical trials (with the exception of Phase I trials) compare the use of a medication or new drug with:
  • a placebo (inactive ‘look-a-like’)
  • other medications, or
  • the standard medical treatment for a patient’s condition

Most trials of cancer drugs are testing the efficacy of a new drug against the current ‘standard of care’ for a specific form of cancer.
 
Trials vary in size from a few dozen patients and one researcher to tens of thousands of patients and hundreds of researchers.

Drug Trial Phases

There are general four phases of drug testing involved in bringing a drug to market.  The drug is usually approved for sale by the national regulatory authority after successful completion of Phase III.  

Phase I

Phase I trials are the first stage of testing a new drug in humans. It is a stage designed to assess the safety and tolerability of a new drug. Usually the drug is administered to a small sample of people (20 to 50) in groups of 3 to 6 at a time, with very careful monitoring by fully trained health care professionals.  Most of the monitoring occurs in the out-patient setting.  Phase I trial subjects often require hospital admission for 1 to 2 nights to be observed closely and to allow for blood (pharmacokinetic) sampling to measure drug levels.  People who enter Phase I trials at an earlier time point typically receive lower doses of the drug.  If, after several ‘half-lives’ of the drug have passed and no severe or limiting toxicities occur, then another group of 3 to 6 people is enrolled at a slightly higher dose of the study drug. (A half-life of a drug is the amount of time it takes before half of the active elements are either eliminated or broken down by the body.)
 
This is the phase when the appropriate dose (and frequency of use) is determined.  ‘Dose escalation’ is a term used to describe the process of administering larger and larger doses of the drug to different groups of patients, with all patients being closely monitored for safety.  In a Phase I trial, the goal is to recommend a dose that is optimal for subsequent use in Phase II trials.  The recommended dose ideally is one that can achieve the desired anti-cancer effects while minimizing side effects.

Phase II

With the initial safety of a drug confirmed in Phase I, Phase II drug trials are performed on larger groups of patients with more of the focus going to determining the effectiveness of the drug.  When the development process for a new drug fails, it usually occurs during Phase II trials when it is concluded that the drug does not work as planned, or it has too many toxic side effects. 

Phase III

These are trials that are typically randomized (each patient is randomly assigned to receive either the test drug or the current ‘standard of care’ for their type of cancer), and they involve multiple hospitals/facilities.  The size of group is typically in the range of 300 to 3,000.  These trials are expensive, time-consuming and challenging to set up, but if the results are positive for the drug, a Phase III trial is considered a definitive assessment of a drug’s effectiveness.

Phase IV

Phase IV trials often have different objectives.  They can be testing the long-term safety of the drug, testing the drug against different populations (e.g., people with specific health conditions) or testing the drug in combination with different drugs.  Because Phase IV trials involve many more people (and usually a much longer time period), there is a much better opportunity to evaluate and document side effects.

New Drug Development Timeline

Below is an illustration of the generally-accepted timeline for developing, testing, and bringing a new drug to market.


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